β2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf
β2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf
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DOI：
10.1074/jbc.m003213200
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发表时间：
2000-08-18
影响因子：
4.8
通讯作者：
Stork, PJS
中科院分区：
文献类型：
--
作者：
Schmitt, JM;Stork, PJS
G 蛋白偶联受体可以通过刺激丝裂原激活蛋白 (MAP) 激酶级联来诱导细胞增殖。异三聚体 G 蛋白由 α 和 β γ 亚基组成，可以独立向多种细胞内信号传导途径（包括激活 MAP 激酶的信号传导途径）发出信号。在这项研究中，我们检查了异丙肾上腺素（β(2)-肾上腺素能受体 (β(2)AR) 的激动剂）刺激细胞外信号调节激酶 (ERK) 的能力。使用表达内源性 β(2)AR 的 HEK293 细胞，我们发现异丙肾上腺素通过 β(2)AR 刺激 ERK。异丙肾上腺素的这种作用需要 cAMP 依赖性蛋白激酶，并且对百日咳毒素不敏感，表明需要 G α 激活 cAMP 依赖性蛋白激酶。有趣的是，β(2)AR 可激活小 G 蛋白 Rap1 和 Res，但只有 Rap1 能够与 Raf 同工型偶联。 beta(2)AR 抑制 Ras 依赖性的 Ras 亚型 Raf-1 和 B-Raf 激活，而异丙肾上腺素激活 Rap1 则招募并激活 B-Raf。 ERK 的 beta(2)AR 激活不会被 RasN17（Ras 的干扰突变体）的表达所阻断，但会被 RapN17 或 Rap1GAP1 的表达所阻断，这两者都会干扰 Rap1 信号传导。我们认为异丙肾上腺素可以通过这些细胞中的 Rap1 和 B-Raf 激活 ERK。
G protein-coupled receptors can induce cellular proliferation by stimulating the mitogen-activated protein (MAP) kinase cascade. Heterotrimeric G proteins are composed of both alpha and beta gamma subunits that can signal independently to diverse intracellular signaling pathways including those that activate MAP kinases. In this study, we examined the ability of isoproterenol, an agonist of the beta(2)-adrenergic receptor (beta(2)AR), to stimulate extracellular signal-regulated kinases (ERKs). Using HEK293 cells, which express endogenous beta(2)AR, we show that isoproterenol stimulates ERKs via beta(2)AR. This action of isoproterenol requires cAMP-dependent protein kinase and is insensitive to pertussis toxin, suggesting that G alpha(s) activation of cAMP-dependent protein kinase is required. Interestingly, beta(2)AR activates both the small G proteins Rap1 and Res, but only Rap1 is capable of coupling to Raf isoforms. beta(2)AR inhibits the Ras-dependent activation of both Raf isoforms Raf-1 and B-Raf, whereas Rap1 activation by isoproterenol recruits and activates B-Raf. beta(2)AR activation of ERKs is not blocked by expression of RasN17, an interfering mutant of Ras, but is blocked by expression of either RapN17 or Rap1GAP1, both of which interfere with Rap1 signaling. We propose that isoproterenol can activate ERKs via Rap1 and B-Raf in these cells.